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This paper describes
the structure-based design of a preliminary drug candidate against COVID-19
using free software and publicly available X-ray crystallographic structures.
The goal of this tutorial is to disseminate skills in structure-based drug
design and to allow others to unleash their own creativity to design new drugs
to fight the current pandemic. The tutorial begins with the X-ray
crystallographic structure of the main protease (Mpro) of the SARS coronavirus
(SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software
to modify the substrate to create a cyclic peptide inhibitor within the Mpro
active site. Finally, the tutorial uses the molecular docking software AutoDock
Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV
Mpro and the highly homologous SARS-CoV-2 Mpro. The supporting information (supplementary material) provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics.
An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872]
describes the synthesis of the cyclic peptide and the experimental validation
as an inhibitor of SARS-CoV-2 Mpro.